By Prajakta ShindeBy Prajakta Shinde

The process by which different kind of organism

develop from earlier form or

simply it’s a gradual development.

What is evolution?

All living organisms have the capacity to defend themselves against

invasion by pathogens. The number of mechanisms that have evolved for immune protection is remarkable.

Innate defense mechanisms are found in all living things, while adaptive immunity grounded on somatically generated immunoglobulin (Ig), T-cell receptors (TCR), and the major histocompatibility complex (MHC) is only present in jawed vertebrates.

Because of clonal selection, positive and negative selection in the thymus, MHC-regulated initiation of all adaptive responses, and so on, the major elements of the adaptive immune system are locked in a co-evolving Ig-TCR-MHC unit.

Introduction

This system was superimposed onto an innate system inherited from primitive invertebrates, from which some innate molecules were co-opted for the initial phase of the adaptive response and others for effector mechanisms at the completion of adaptive responses.

The basic protective strategy of an innate immune system is to constitutively produce generic receptors that recognize conserved patterns on different classes of pathogens to trigger an inflammatory response that limits pathogen invasion.

Specific adaptive immunity, by contrast, depends upon the somatic diversification of antigen-receptor genes to generate a vast repertoire of cells, each of which expresses a different antigen receptor.

Lymphocytes, the specialized cell type of the adaptive immune system, use their cell-surface receptors to recognize antigenic configurations of specific pathogens and then respond to the antigen triggering by clonal amplification, cellular differentiation, and production of antibodies with the same antigen binding specificity.

An antibody (AB), also known as an immunoglobulin (Ig), is a

large, Y-shape protein produced by plasma cells that is used by the immune system to identify and neutralize pathogens such as bacteria and viruses.

The antibody recognizes a unique molecule of the harmful agent, called an antigen, via the variable region.

Immunoglobulin

Is composed of four polypeptide chains (two heavy [H] and two light [L]) joined into a macromolecular complex via several disulfide bonds.

Each chain is composed of a linear combination of Igsf domains, much like the TCR and almost all molecules studied to date can be expressed in secreted or trans membrane forms. 

Ig heavy chain isotype:

An isotype refers to any related proteins from a particular gene family. In immunology, the “immunoglobulin isotype" refers to the phenotypic variations in the constant regions of the heavy and light chains. In humans, there are five heavy chain isotype and two light chain isotype:

Heavy chain isotype ex; α - IgA 1, 2 δ - IgD γ - IgG 1, 2, 3, 4 ε - IgE μ - IgM

Functional & Structural evolution of immunoglobulin

Sequences of IgH-chain C-region genes, however, are

not well conserved in evolution and insertions and deletions in loop segments occur more often in C than in V domains.

The secretory µ H chain is found in all vertebrates

and consists of one V and four C1 domains, and is heavily glycosylated.

H chains associate with each other and with L chains through disulfide bridges in most species, and IgM subunits form pentamers or hexamers in all vertebrate classes except teleost fish where tetramers are clearly found.

The µ CH4 domain is most evolutionarily conserved, especially in its C-terminal region.

IgM

There are several µ-specific residues in each of the

four CH domains among vertebrates suggesting a continuous line of evolution, which is supported by phylogenetic analyses.

Modification occurs by splicing eg;splicing of teleost fish µ mRNA takes place at the end of CH3 exon,In holostean fish cryptic splice donor sites are found in the CH4 sequence ,in the bowfin there is another cryptic splice donor site in CH3

A dimer found in the serum of nurse sharks. composed of two H chains, each containing a V

domain generated by rearrangement and five constant C1 domains.

Ig NAR(new antigen receptor)

Originally discovered as a second Ig class in the

skate Raja kenojei named IgR, this non-µ isotype was later cloned from another skate species and designated IgX .

The IgX H-chain C region consists of two Ig domains and an unusual cysteine-rich C-terminal segment

Later, cDNAs encoding long forms of IgX were detected in sandbar shark (called IgW) and nurse sharks (called IgNARC because of the C-domain similarities to IgNAR).

IgR/IgNARC/IgW/IgX

IgD was thought to be a recently evolved Ig. a novel Ig first discovered in channel catfish and later in

other teleost's is homologous, in part, to δ H chains. Phylogenetic trees indicate a relationship between teleost

and mammalian IgD primarily because of the similarity between fish δ 5 and human δ 2 domains .

Specific differences in cod IgD such as deletion of some d domains, a tandem duplication, and translocations of part of the locus, developed after divergence of the catfish and salmon lineages.

Ig D Homologues

V D J segments

A rearranged VH gene consists of a leader followed

by four framework regions and three CDRs. In all species, functional V genes are assembled by

rearrangement and joining of germline V, D, and J elements.

In teleost, seven VH families have been characterized in the catfish, each containing up to seven to ten genes.

VH Regions

Xenopus has at least 11 V families. There are actually fewer functional human VH than

in many ectotherms. Dynamic reorganization of the H-chain V regions

seems to have occurred at least eight times between 133 and 10 million years ago.

D segments are always present in one of the two loci

encoding an Ig/TCR heterodimer . D segments have been preserved throughout

evolution.

D segments

J segments encode the G strand of an Igsf domain,

which contains a highly conserved diglycine bulge that is vital for the structure of the dimeric receptor.

J segment

L chains can be classified phylogenetically not only by

their sequence similarity, but also by the orientation of their V and J RSS.

Ig light chain isotype light chain

Κ

λ σ

Ig light chain

The joining (J) chain is a small polypeptide,

expressed by mucosal and glandular plasma cells, which regulates polymer formation of IgA and IgM.

J chain

.Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region.

The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments .

V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains.

Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes ofmammals.

In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain).

As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.

V(D)J recombination

B cells begin to proliferate rapidly. In these rapidly

dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation(SHM).

SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains

Somatic hypermutation(SHM)

Adaptive immunity require Ig & TCR genes based

on the RAG1 RAG2 enzymes (recombinase activating gene) & their binding to RSS( recombination sequence signal)

Both RAG & RSS formed part of a retrotransoposone early in evolution.

Adaptive immunity with TCR & Ig appear suddenly in cartilaginous fishes both VLR (variable Lucien rich receptor) is present in jawless fish.

Big Bang/Band Hypothesis

Jawless fish Hagfish, Lamprey do no have organized lymphoid tissue no primary immune response or memory T or B cells .